Reacción #86682

Ecuación de reacción

6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate

methanesulfonamide

2-methyltetrahydrofuran

potassium phosphate tribasic

L-cysteine

sodium chloride

→

title compound

Rendimiento 94.6%

N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide

Rendimiento 94.6%

Disolventes

water

Tetrahydrofuran

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroThe flask was purged with argon for not less than 90 minutes
2. 2
   Otro2-Methyltetrahydrofuran (70 mL) was taken in a 100-mL round bottom flask
3. 3
   Otropurged with argon for not less than 30 minutes
4. 4
   OtroA 250-mL, round bottom flask equipped with a magnetic stir bar
5. 5
   Otropurged with argon for not less than 60 minutes
6. 6
   Temperaturahas been cooled to the room temperature
7. 7
   TemperaturaThe temperature of the 450-mL flask was raised to 90° C.
8. 8
   workup.STIRRINGthe contents were stirred for 14 hours
9. 9
   Temperaturato cool down to 70° C.
10. 10
    workup.ADDITIONdiluted with ethyl acetate (190 mL)
11. 11
    workup.STIRRINGstirred for 3 hours at 70° C.
12. 12
    Temperaturacooled to the room temperature
13. 13
    workup.STIRRINGstirred for an additional 4 hours
14. 14
    Filtraciónfiltered through a fine frit
15. 15
    Filtraciónfilter funnel
16. 16
    Lavadorinsed with ethyl acetate (90 mL)
17. 17
    Otroto obtain 29.4 g of light brown solid
18. 18
    Otroequipped with an overhead stirrer
19. 19
    workup.STIRRINGThe reaction mixture was stirred for 2 hours at 50° C. under a slight positive pressure of argon
20. 20
    OtroThe reaction mixture was transferred to a 500-mL separatory funnel
21. 21
    FiltraciónThe organic layer was filtered through an approximately 2-inch pad of diatomaceous earth
22. 22
    Lavadorinsed with tetrahydrofuran (45 mL)
23. 23
    Otroto obtain a clear, light yellow solution
24. 24
    ConcentraciónThe organic layer was concentrated to a total weight of 45.59 g
25. 25
    workup.ADDITIONA portion of this organic solution (41.58 g) was charged to a 250-mL, 3-neck round bottom flask
26. 26
    Otrofitted with an overhead stirrer
27. 27
    workup.ADDITIONEthyl acetate (80 mL) was added over 6 hours by a pump
28. 28
    workup.STIRRINGwith constant stirring at room temperature
29. 29
    FiltraciónThe product was collected by filtration
30. 30
    Lavadorinsed with ethyl acetate (20 mL)
31. 31
    Otrodried in a vacuum oven for 2 hours

Procedimiento

A 450-mL, stainless steel Parr® pressure reactor equipped with an overhead stirrer was charged with tris(dibenzylideneacetone)dipalladium(0) (0.105 g, 0.115 mmol), di-tert-butyl(2′,4′,6′-triisopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (0.133 g, 0.275 mmol) and milled potassium phosphate tribasic (5.35 g, 25.2 mmol). The flask was purged with argon for not less than 90 minutes. 2-Methyltetrahydrofuran (70 mL) was taken in a 100-mL round bottom flask, purged with argon for not less than 30 minutes and was transferred to the 450-mL reactor using a cannula under argon atmosphere. The contents of the 450-mL reactor were heated to 80° C. and stirred at this temperature for 30 minutes. A 250-mL, round bottom flask equipped with a magnetic stir bar was charged with 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl 1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate (16.0 g, 22.9 mmol), methanesulfonamide (2.61 g, 27.5 mmol) and 2-methyltetrahydrofuran (155 mL), purged with argon for not less than 60 minutes. This solution was transferred to the 450-mL reactor that has been cooled to the room temperature using a cannula under argon atmosphere. The temperature of the 450-mL flask was raised to 90° C. and the contents were stirred for 14 hours. The reaction mixture was allowed to cool down to 70° C., diluted with ethyl acetate (190 mL) and stirred for 3 hours at 70° C., cooled to the room temperature, stirred for an additional 4 hours, filtered through a fine frit filter funnel and rinsed with ethyl acetate (90 mL) to obtain 29.4 g of light brown solid. A portion of this solid (13.04 g) was transferred to a 500-mL, 3-neck round bottom flask equipped with an overhead stirrer and a thermocouple. Tetrahydrofuran (175 mL) was added, followed by the addition of water 50 mL containing L-cysteine (0.63 g) and sodium chloride (5.5 g). The reaction mixture was stirred for 2 hours at 50° C. under a slight positive pressure of argon. The reaction mixture was transferred to a 500-mL separatory funnel and the aqueous layer was discarded. The organic layer was filtered through an approximately 2-inch pad of diatomaceous earth and rinsed with tetrahydrofuran (45 mL) to obtain a clear, light yellow solution. The organic layer was concentrated to a total weight of 45.59 g. A portion of this organic solution (41.58 g) was charged to a 250-mL, 3-neck round bottom flask fitted with an overhead stirrer. Ethyl acetate (80 mL) was added over 6 hours by a pump with constant stirring at room temperature. The product was collected by filtration, rinsed with ethyl acetate (20 mL) and dried in a vacuum oven for 2 hours to obtain 3.17 g of the title compound (>99.8 pure and 94.6% potent vs. standard).

Fuente